PDF file - 1105K, Supplemental Figure 7. KISS1 inhibits glucose uptake and activation of AMPK. A, Glucose uptake by C8161.9Vector (Vec), C8161.9KFMΔSS, C8161.9KFM and C8161.9KFM/shPGC1α cells was measured using 2-deoxyglucose uptake and normalized to total protein. B, C8161.9Vector, C8161.9KFM and C8161.9KFMdeltaSS cells were treated with AICAR followed by Western blot with antibodies for AMPK, phospho-AMPK (Thr172), mTOR , phospho-mTOR (Ser2448), KISS1 and GAPDH.
ARTICLE ABSTRACT
Cancer cells tend to utilize aerobic glycolysis even under normoxic conditions, commonly called the “Warburg effect.” Aerobic glycolysis often directly correlates with malignancy, but its purpose, if any, in metastasis remains unclear. When wild-type KISS1 metastasis suppressor is expressed, aerobic glycolysis decreases and oxidative phosphorylation predominates. However, when KISS1 is missing the secretion signal peptide (ΔSS), invasion and metastasis are no longer suppressed and cells continue to metabolize using aerobic glycolysis. KISS1-expressing cells have 30% to 50% more mitochondrial mass than ΔSS-expressing cells, which are accompanied by correspondingly increased mitochondrial gene expression and higher expression of PGC1α, a master coactivator that regulates mitochondrial mass and metabolism. PGC1α-mediated downstream pathways (i.e., fatty acid synthesis and β-oxidation) are differentially regulated by KISS1, apparently reliant upon direct KISS1 interaction with NRF1, a major transcription factor involved in mitochondrial biogenesis. Since the downstream effects could be reversed using short hairpin RNA to KISS1 or PGC1α, these data appear to directly connect changes in mitochondria mass, cellular glucose metabolism, and metastasis. Cancer Res; 74(3); 954–63. ©2013 AACR.
